Traumatic brain injury (TBI) is a leading cause of death and long-term disability in the US and around the world. Over 1.5 million Americans sustain traumatic brain injuries each year. Recent research findings point to impact-induced TBI and repetitive concussion as predisposing factors that increase risk of developing chronic traumatic encephalopathy (CTE) and chronic traumatic encephalomyelopathy (CTEM), two newly- recognized and related neurodegenerative disorders. The neuropathology of CTE/CTEM includes widespread tau-associated neurofibrillary tangles with characteristic perivascular and deep sulcal distribution, profound myelinated fiber loss, and persistent neuroinflammation. We hypothesize that biomechanical forces transmitted to the brain during closed head impact-induced TBI generate shearing stress that disrupt microvascular integrity, activate neuroinflammatory responses, and initiate pathogenic cascades that lead to persistent TBI and late-emerging CTE/CTEM neuropathology. We propose two aims to investigate this hypothesis. In Aim 1, we will develop, characterize, and validate a murine closed-head impact neurotrauma (mINT) model system. In Aim 2, we will characterize temporal and regional patterns of microvascular disruption, neuroinflammation, and CTE/CTEM-linked neuropathology using the mINT model system developed in Aim 1. The proposed multidisciplinary project will investigate the mechanistic pathobiology of impact-induced TBI and CTE/CTEM using a custom closed-head impact delivery system that is capable of delivering single or repeat impacts across a range of scaled velocities corresponding to clinically relevant human injury. Comprehensive neuropathological analysis and immunophenotyping will be used to characterize and localize neuroinflammation and focal tauopathy. Brain microvascular integrity will be assessed using a well-established classical techniques to investigate alterations in blood-brain barrier (BBB) permeability. The results of these studies will advance understanding of impact-induced TBI and later development of CTE/CTEM. Insight gained from this work will also facilitate development of urgently needed diagnostics and therapeutics for these devastating disorders.